A Double Punch of Viruses & Immunotherapy Could Improve Outcomes for Cancer Patients

Activating the body's own immune system to fight cancer is the goal of immunotherapy. It's less toxic than chemotherapy and works with our body's natural defenses. The trouble is, it doesn't work for most patients — only about 40% of cancer patients get a good response from immunotherapy. But coupling it with another type of cancer therapy just might deliver the punch that's needed to knock out cancer.

That combination therapy is what a group of scientists from Memorial Sloan-Kettering Cancer Center in New York City has been testing. They used an inactivated virus to provoke the immune system to fight cancer, and in the process, it increased the effectiveness of immunotherapy.

The researchers effectively delivered a cancer-beating one-two punch by triggering a delicate and intricate dance within the immune system. The results of the study, by first author Peihong Dai and her colleagues, were published May 19 in the journal Science Immunology.

The Players

T lymphocytes are a type of white blood cells active in fighting infection and cancer. They are further divided into subtypes based on the proteins on their surface, and the different T cells work together to help create the intricacies of our immune response.

One type of CD4 T cells is helper T cells, which assist other T cells in the immune response.
CD8 T cells are killer cells. They respond by killing what they recognize as foreign.
PD-1 is a checkpoint protein found on T cells. It acts as a type of "off switch" to keep T cells from attacking other cells in the body. That's a good thing — except when we need the T cells to fight and kill cancer.

In cancer, we would like the PD-1 function turned off so that the T cells can attack the cancer cells. One of the newer cancer treatments uses checkpoint inhibitors to do this. These are biologic agents (they're not drugs) similar to those already in the body that work on the checkpoint proteins on T cells. Anti-PD-1 is one example of a checkpoint inhibitor used as an immunotherapeutic cancer agent.

Two problems with checkpoint inhibitors are that they can allow the immune system to attack some normal organs in the body, and they work in only about 15–20% of patients.

Virotherapy, the use of viruses to infect and kill cancer cells, is another developing field of cancer therapy. In simplest terms, as the viruses replicate inside cells, they kill them. If they replicate in cancer cells, they can kill them, too.

Virotherapy has its own problems, though. Our body eventually mounts an immune response against it, and the viruses (herpesvirus, for example) have to be engineered so that they don't cause an infection in non-cancer cells while making sure the non-disease causing virus still replicates and kills the cancer cells.

Cancer-Killing Teamwork

The goal of the new research was to alter the immune response to checkpoint inhibitors so that the body would destroy cancer cells, but still not attack healthy organs. That meant that checkpoint proteins on T cells had to be quieted and CD8 killer cells activated. To do this, the researchers turned to virotherapy to boost the immune response against the tumor.

Testing their technique on mice with melanoma and colon cancer, the researchers injected their tumors with a modified vaccinia virus called iMVA that could not cause viral disease.

A Double Punch of Viruses & Immunotherapy Could Improve Outcomes for Cancer Patients — *Image by Carla Schaffer/AAAS*

The injection of virus increased the numbers of CD8 killer T cells at the tumor, as well as CD103 dendritic cells. The CD103 cells brought bits of the virus to lymph nodes that, in turn, sent more CD8 killer T cells as well as helper CD4 cells to the tumor.

Twenty-five days after the scientists injected the tumors with the virus, 60% of the treated mice were alive, while none of the non-injected mice were alive. The researchers saw even better results when they also treated the mice with checkpoint inhibitors.

Sixty days after treating mice with both intratumor injections of the virus and abdominal injections of checkpoint inhibitors, about 60% were still alive. By 60 days, only 10% of the mice who only received injections of the virus (without checkpoint inhibitors) were alive. All non-treated mice were dead.

What's more remarkable, is that by this 60-day time point, the mice who received both the intra-tumor virus injections and the checkpoint inhibitor showed delayed growth of their tumors or complete elimination of their tumors.

iMVA injection with a checkpoint inhibitor effectively "released the brakes" on T cell activity that checkpoint proteins were controlling, letting them participate in the anti-tumor response, and that enhanced tumor-killing and improved survival better than either therapy alone.

Dai and her colleagues plan to try their combination approach on breast and prostate cancers next, two cancers known to be even more resistant to immunotherapy than the melanoma and colon cancers used in this study.

For years, treating cancer has meant combinations of potent chemotherapy drugs. Treatment of many cancers has evolved to include the use of immunological agents that help our immune system kill cancer. It appears that, like chemo, the results of immunotherapy can benefit greatly from combined efforts.